Weinberg Adriana, Muresan Petronella, Richardson Kelly M, Fenton Terence, Dominguez Teresa, Bloom Anthony, Watts D Heather, Abzug Mark J, Nachman Sharon A, Levin Myron J
University of Colorado Anschutz Medical Center, Aurora, Colorado, United States of America.
Statistical and Data Analysis Center, Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts, United States of America.
PLoS One. 2015 Apr 13;10(4):e0122431. doi: 10.1371/journal.pone.0122431. eCollection 2015.
Influenza infections have high frequency and morbidity in HIV-infected pregnant women, underscoring the importance of vaccine-conferred protection. To identify the factors that determine vaccine immunogenicity in this group, we characterized the relationship of B- and T-cell responses to pandemic H1N1 (pH1N1) vaccine with HIV-associated immunologic and virologic characteristics. pH1N1 and seasonal-H1N1 (sH1N1) antibodies were measured in 119 HIV-infected pregnant women after two double-strength pH1N1 vaccine doses. pH1N1-IgG and IgA B-cell FluoroSpot, pH1N1- and sH1N1-interferon γ (IFNγ) and granzyme B (GrB) T-cell FluoroSpot, and flow cytometric characterization of B- and T-cell subsets were performed in 57 subjects. pH1N1-antibodies increased after vaccination, but less than previously described in healthy adults. pH1N1-IgG memory B cells (Bmem) increased, IFNγ-effector T-cells (Teff) decreased, and IgA Bmem and GrB Teff did not change. pH1N1-antibodies and Teff were significantly correlated with each other and with sH1N1-HAI and Teff, respectively, before and after vaccination. pH1N1-antibody responses to the vaccine significantly increased with high proportions of CD4+, low CD8+ and low CD8+HLADR+CD38+ activated (Tact) cells. pH1N1-IgG Bmem responses increased with high proportions of CD19+CD27+CD21- activated B cells (Bact), high CD8+CD39+ regulatory T cells (Treg), and low CD19+CD27-CD21- exhausted B cells (Bexhaust). IFNγ-Teff responses increased with low HIV plasma RNA, CD8+HLADR+CD38+ Tact, CD4+FoxP3+ Treg and CD19+IL10+ Breg. In conclusion, pre-existing antibody and Teff responses to sH1N1 were associated with increased responses to pH1N1 vaccination in HIV-infected pregnant women suggesting an important role for heterosubtypic immunologic memory. High CD4+% T cells were associated with increased, whereas high HIV replication, Tact and Bexhaust were associated with decreased vaccine immunogenicity. High Treg increased antibody responses but decreased Teff responses to the vaccine. The proportions of immature and transitional B cells did not affect the responses to vaccine. Increased Bact were associated with high Bmem responses to the vaccine.
流感感染在感染HIV的孕妇中具有高发生率和高发病率，这凸显了疫苗赋予的保护作用的重要性。为了确定决定该群体疫苗免疫原性的因素，我们对B细胞和T细胞对大流行H1N1（pH1N1）疫苗的反应与HIV相关的免疫学和病毒学特征之间的关系进行了表征。在119名感染HIV的孕妇接种两剂双倍剂量的pH1N1疫苗后，检测了她们体内的pH1N1和季节性H1N1（sH1N1）抗体。对57名受试者进行了pH1N1-IgG和IgA B细胞荧光斑点试验、pH1N1和sH1N1干扰素γ（IFNγ）及颗粒酶B（GrB）T细胞荧光斑点试验，以及B细胞和T细胞亚群的流式细胞术表征。接种疫苗后pH1N1抗体增加，但低于先前在健康成年人中所描述的情况。pH1N1-IgG记忆B细胞（Bmem）增加，IFNγ效应T细胞（Teff）减少，而IgA Bmem和GrB Teff没有变化。在接种疫苗前后，pH1N1抗体和Teff彼此之间以及分别与sH1N1血凝抑制抗体（HAI）和Teff显著相关。当CD4⁺细胞比例高、CD8⁺细胞比例低以及CD8⁺ HLA-DR⁺ CD38⁺ 活化（Tact）细胞比例低时，对疫苗的pH1N1抗体反应显著增加。当CD19⁺ CD27⁺ CD21⁻ 活化B细胞（Bact）比例高、CD8⁺ CD39⁺ 调节性T细胞（Treg）比例高以及CD19⁺ CD27⁻ CD21⁻ 耗竭B细胞（Bexhaust）比例低时，pH1N1-IgG Bmem反应增加。当HIV血浆RNA水平低、CD8⁺ HLA-DR⁺ CD38⁺ Tact、CD4⁺ FoxP3⁺ Treg以及CD19⁺ IL-10⁺ B调节细胞比例低时，IFNγ-Teff反应增加。总之，对sH1N1预先存在的抗体和Teff反应与感染HIV的孕妇对pH1N1疫苗接种反应的增加相关，提示异源亚型免疫记忆起重要作用。高比例的CD4⁺ T细胞与反应增加相关，而高HIV复制、Tact和Bexhaust与疫苗免疫原性降低相关。高比例的Treg增加抗体反应，但降低对疫苗的Teff反应。未成熟和过渡性B细胞的比例不影响对疫苗的反应。Bact增加与对疫苗的高Bmem反应相关。
